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com MEDICAL
PROGRESS
Interdisciplinary Care of Children with
Severe Bronchopulmonary Dysplasia
Steven H. Abman, MD1, Joseph M. Collaco, MD, PhD2, Edward G. Shepherd, MD3, Martin Keszler, MD4,
Milenka Cuevas-Guaman, MD5, Stephen E. Welty, MD5, William E. Truog, MD6, Sharon A. McGrath-Morrow, MD, MBA2,
Paul E. Moore, MD7, Lawrence M. Rhein, MD8, Haresh Kirpalani, BM, MSc9, Huayan Zhang, MD9, Linda L. Gratny, MD6,
Susan K. Lynch, MD3, Jennifer Curtiss, RD, LD3, Barbara S. Stonestreet, MD4, Robin L. McKinney, MD4, Kevin C. Dysart, MD9,
Jason Gien, MD1, Christopher D. Baker, MD1, Pamela K. Donohue, MS, ScD2, Eric Austin, MD, MSCI7, Candice Fike, MD7, and
Leif D. Nelin, MD3 on behalf of the Bronchopulmonary Dysplasia Collaborative*

infants born at below 32 weeks gestation.4 Furthermore, BPD

A
dvances in perinatal care have dramatically im-
proved survival of extremely preterm infants and the
incidence of bronchopulmonary dysplasia (BPD) has
not changed over the past few decades, which likely reflects the
impact of increased survival of extremely preterm infants.1 BPD
remains the most common late morbidity of preterm birth,
but many controversies persist regarding how to best define
BPD, grade its severity, and prevent disease.2 Ongoing clini-
cal care and research have largely focused on issues regarding
the pathogenesis and prevention of BPD in preterm infants
with the important goal of reducing the incidence of BPD at
36 weeks corrected age, with a focus on respiratory care related
issues during the early neonatal intensive care unit (NICU)
course.3 However, some preterm infants develop particularly
severe chronic respiratory disease and have related comorbidities
that persist throughout their NICU course and post-discharge,
as reflected by the prolonged need for high levels of respira-
tory support, including mechanical ventilation and high in-
spired oxygen concentrations. The management of infants with
severe BPD (sBPD) has received less attention regarding clini-
cal studies and interventions when compared with preven-
tive strategies, yet these infants constitute a critical population
who remain at high risk for extensive morbidities and late mor-
tality (Figure 1).
Based on consensus recommendations from a National In-
stitutes of Health (NIH) workshop, BPD is commonly defined
by the requirement for supplemental oxygen at 28 days in
BPD Bronchopulmonary dysplasia
CCBs Calcium channel blockers
CPAP Continuous positive airway pressure
FiO2 Fraction of inspired oxygen
GERD Gastroesophageal reflux disease
iNO Inhaled nitric oxide
LRTIs Lower respiratory tract infections
MBD Metabolic bone disease
NICU Neonatal intensive care unit
is divided into 3 severity grades (mild, moderate, or severe)
based on respiratory support needs at 36 weeks postmenstrual
age (PMA) (Table I). The incidence of sBPD is inversely cor-
related with gestational age and remains 16% for all infants
born at <32 weeks (Table I).5 Unfortunately, high-quality evi-
dence on which to base the care for infants and children with
sBPD and consensus care guidelines are lacking. These knowl-
edge gaps have contributed to marked variability in care within
and between NICUs throughout the country. Current NIH defi-
nitions of BPD are almost exclusively focused on NICU-
related issues, with limited discussion regarding long-term
respiratory outcomes throughout infancy, childhood, and adult-
hood. In addition, the classification of sBPD is very broad and
fails to differentiate between proposed phenotypes of infants
with a persistent oxygen requirement and/or need for
continuous positive airway pressure (CPAP) or high flow nasal
cannula at 36 weeks postconceptual age who have relatively
less severe respiratory disease (type 1 sBPD; Table I) from those
with more extreme BPD (or type 2 sBPD), who remain
ventilator-dependent and more often have severe complica-
tions, including pulmonary hypertension, poor growth, and
neurodevelopmental problems. Understanding distinct ante-
natal, early postnatal, genetic, or epigenetic factors, or
comorbidities that contribute to sBPD, especially the more
severe phenotype (type 2 sBPD), are critical for enhancing late
outcomes in this subgroup.
Clinical needs of infants with type 2 sBPD who require
ongoing respiratory support beyond term corrected age are
diverse and complex, and management strategies that
From the 1University of Colorado Anschutz Medical Center and Children’s Hospital
Colorado, Aurora, CO; 2Johns Hopkins Medical Institutions, Baltimore, MD;
3Nationwide Children’s Hospital, The Ohio State University, Columbus, OH; 4Alpert
Medical School of Brown University, Women and Infants Hospital, Providence, RI;
5Texas Children’s Hospital, Baylor College of Medicine, Houston, TX; 6Children’s

NIH National Institutes of Health Mercy Hospitals and Clinics, University of Missouri-Kansas City School of Medicine,
Kansas City, MO; 7Vanderbilt University School of Medicine, Nashville, TN;
PEEP Positive end expiratory pressure 8University of Massachusetts School of Medicine, Worcester, MA; and 9Children’s

PFTs Pulmonary function testing Hospital of Philadelphia and University of Pennsylvania Perelman School of
PH Pulmonary hypertension Medicine, Philadelphia, PA

PMA Postmenstrual age *List of additional members of the BPD Collaborative is available at www.jpeds.com
(Appendix).
RSV Respiratory syncytial virus
S.A. serves on the Editorial Board of The Journal of Pediatrics. The other authors
sBPD Severe BPD declare no conflicts of interest.
Ti Inspiratory time
Vt Tidal volume 0022-3476/$ - see front matter. © 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org10.1016/j.jpeds.2016.10.082

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the care of children with sBPD. In this review, we present an

interdisciplinary approach to patients with sBPD and their fami-
lies throughout the NICU and outpatient courses. Emphasis
is placed on the rationale for developing the team approach
to chronic care as well as highlighting key gaps in knowledge
in our care for infants with sBPD, which would likely improve
with multicenter investigations.

Incidence and Etiology of sBPD

Figure 1. Imaging of sBPD: Chest radiograph (left) and image
from computed tomography (CT) scan illustrate radiographic
abnormalities of type 2 sBPD. Note the severe cystic disease
present on the CT scan.
optimize survival and long-term outcomes are controversial
and uncertain. Several factors contribute to increased mor-
bidity and mortality in this population. First, there are few
evidence-based strategies to improve outcomes. Second, pa-
tients with chronic ventilator-dependent BPD have histori-
cally been cared for in acute care settings. Management
strategies for chronic disease differ considerably from acute re-
spiratory failure, especially regarding approaches to mechani-
cal ventilation. When compared with approaches toward acute
respiratory failure, neonatal and pediatric intensivists may have
less experience with ventilator management of infants with
severe chronic lung disease. Most importantly, poor commu-
nication between providers, subspecialists, nursing staff, and
families during prolonged hospitalization may lead to incon-
sistent care and adverse outcomes. High staff turnover and in-
frequent communication among the doctors and bedside staff
as well as between parents and the medical team may con-
tribute to these inconsistencies. These infants have complex
clinical courses with multiple morbidities, including fre-
quent hospitalizations throughout childhood, and often with
poor continuity of care. Interdisciplinary care teams have the
potential to alleviate many of these issues and improve out-
comes for these infants.
Based on these concerns, a group of clinicians from
interdisciplinary care programs for infants with sBPD at
several major medical centers, including neonatologists,
pulmonologists, critical care physicians, gastroenterologists,
nurse specialists, and others, formed the “BPD Collabora-
tive,” to address controversies and promote research to enhance
Although marked improvements in care have led to milder re-
spiratory courses for most preterm infants, sBPD remains a
major problem. In the validation study from the Eunice Kennedy
Shriver National Institute of Child Health and Human Devel-
opment Neonatal Research Network, the incidence of sBPD
was 16% in infants born at <32 weeks and weighing <1000 g
(Table I).5 Reports using birth cohorts from Scandinavia found
that the incidence of sBPD was 25% in infants born at <27
weeks gestation in Sweden, and 20% in infants born at <28
weeks in Norway.6,7 The Children’s Hospital Neonatal Con-
sortium reported a 16% incidence of sBPD of patients born
at <32 weeks, of whom 91% survived to discharge, 66% were
discharged on supplemental oxygen, 4% on mechanical ven-
tilation, and 5% received tracheostomy.8 The BPD Collabora-
tive reported a point prevalence of sBPD of 36.5% with a range
across centers of 11%-58%, and 41% of the patients with sBPD
had type 2 sBPD with a range of 0%-68%.9 Using an esti-
mated incidence of sBPD of 16% for infants born at <32 weeks
suggests that ~13 000 patients develop sBPD annually in the
US alone.5
Epidemiologic data are limited, but estimates suggest that
roughly 8000 children in the US receive mechanical ventila-
tion at home.10 Based on 2011 data from the state of Penn-
sylvania’s Ventilator Assisted Children’s Home Program, 36%
of ventilator-dependent children were diagnosed with chronic
lung disease, 77% of these specifically with the diagnosis of
sBPD.10 From these data, it can be extrapolated that ~2000
infants and children with sBPD are dependent on mechani-
cal ventilation at home in the US.
The exact pathogenic mechanisms underlying the develop-
ment of sBPD in preterm infants and factors that favor the de-
velopment of sBPD are uncertain. Similarly, factors that
contribute to the receipt of prolonged mechanical ventila-
tion within the subgroup with type 2 sBPD are uncertain. The
incidence of sBPD is inversely related to gestational age at

Table I. BPD definition with severity

Postdischarge
Relative incidence mortality
Definition (Data from (Data from
BPD severity (Modified from Jobe and Bancalari4) Ehrenkranz et al5) Ehrenkranzet al5)
None O2 treatment <28 d and breathing room air at 36 wk PMA or discharge home, whichever comes first 23.1% 1.8%
Mild O2 treatment at least 28 d and breathing room air at 36 wk PMA or discharge home, whichever comes first 30.3% 1.5%
Moderate O2 treatment at least 28 d and receiving <30% O2 at 36 wk PMA or discharge home, whichever comes first 30.2% 2.0%
Severe (type 1) O2 treatment at least 28 d and receiving ≥30% O2 or nasal CPAP/HFNC at ≥36 wk PMA 16.4% 4.8%
Severe (type 2) O2 treatment at least 28 d and receiving mechanical ventilation at ≥36 wk PMA.

HFNC, high flow nasal cannula; O2, oxygen.

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birth.6,11,12 Male infants are more likely to develop sBPD and
the need for mechanical ventilation. Patent ductus arterio-
sus, sepsis, and surgical necrotizing enterocolitis are strongly
associated with the development of sBPD.11 A recent preclini-
cal study suggests dose-related effects of antenatal endotoxin
as a model for experimental chorioamnionitis that is suffi-
cient to induce sBPD, and moderate oxygen treatment actu-
ally improved lung structure rather than worsening respiratory
outcome, suggesting the complexity of pre- and postnatal events
in driving BPD phenotypes.13
The genetics and epigenetic, or gene/environmental factors,
underlying the risk for sBPD remain to be determined, however,
recent twin studies have demonstrated a genetic component
to the development of BPD in general,14,15 and there are an in-
creasing number of gene-targeted studies finding specific mu-
tations in genes associated with lung development, immunity,
and oxidative stress associated with BPD in preterm infants.16-21
However, specific genes that increase the risk for sBPD remain
unknown. In particular, data are lacking that specifically address
whether distinct genetic, epigenetic, or other etiologic mecha-
nisms contribute to the development of sBPD in compari-
son with milder forms of BPD. In addition, there is a clear need
to develop biomarkers and other predictors for the early iden-
tification of preterm newborns who are at risk for BPD and
more specifically for sBPD.
Clinical Features of sBPD
Although perhaps less common than in the past, infants with
sBPD present persistent challenges, raise many questions re-
garding optimal strategies for enhancing outcomes, and may
at times present significant ethical dilemmas. Furthermore, there
is limited high quality evidence on which to base clinical man-
agement of the patient with sBPD. Evaluation of the patient
with sBPD can include a variety of studies discussed herein,
which should be guided by clinical presentation. In the extreme
preterm infant with type 2 sBPD with the usual NICU course,
there is little need to exclude other potential causes of chronic
lung disease. In the infant with an atypical presentation or
NICU course, potential causes of chronic neonatal respira-
tory failure include surfactant protein deficiency, gastroesopha-
geal reflux disease (GERD), cystic fibrosis, immune deficiency,
anatomic heart disease, pulmonary infection, H-type tracheo-
esophageal fistula, primary ciliary dyskinesia, and other de-
velopmental lung diseases. Evaluations may include
bronchoscopy, echocardiogram, esophageal pH and imped-
ance probes, genetic testing, chest computed tomography scan,
lung biopsy, and other studies.
The NIH consensus statement that defined BPD severity4
did not address the wide range of disease severity within the
group classified as sBPD. In 2003, the American Thoracic
Society published a consensus statement pertaining to the care
of children with BPD emphasizing the need for an interdis-
ciplinary approach to address the multiorgan sequelae of pre-
mature birth.22 More specifically, infants with type 2 sBPD are
at increased risk for adverse comorbidities including
neurodevelopmental impairment, pulmonary hypertension
(PH), GERD, feeding difficulties, airways disease, retinopa-
thy of prematurity, and systemic hypertension. These
comorbidities frequently complicate the course in sBPD, require
the involvement of multiple subspecialists, and, when not in-
tegrated into the overall management plan, can further exac-
erbate gaps in communication and care. In centers that have
adopted an interdisciplinary approach to care, survival for this
subset of infants is over 75%-80% at discharge.9,23 Because of
the low incidence of type 2 sBPD at any single center, this popu-
lation remains understudied, and many gaps in knowledge
(Table II24) and controversies exist regarding optimal clinical
strategies to improve outcomes in this subgroup of infants.
Mechanical Ventilation in sBPD
The strategy for respiratory support in the acute phases of
extreme prematurity is to avoid unnecessary intubation and

Table II. Identification of unique research needs to enhance our understanding of sBPD (Modified from Collaco et al24)
Epidemiology
1. To quantify the current incidence of sBPD among preterm infants
2. To understand the natural history and outcomes of sBPD by large prospective studies in different areas of the world
3. To understand the economic impact of sBPD on families and society
4. To understand the impact of sBPD on quality of life in infants and their families
Risk factors
1. To identify prenatal and postnatal factors that increase risk of developing sBPD in preterm infants
2. To identify risk factors that may exacerbate sBPD in preterm infants, including viral infections, lower respiratory tract disease, upper airway obstruction,
intermittent hypoxia and hypercarbia, feeding problems with aspiration, and gastroesophageal reflux
3. To understand the role of pulmonary vascular disease in determining the severity of BPD
Pathophysiology
1. To further identify clinical, epidemiologic and biomarker features to better phenotype subtypes of sBPD
2. To identify genetic and epigenetic factors that influence the development and severity of sBPD
Diagnosis
1. To determine the best non-invasive studies for diagnosis and following infants with sBPD
Management
1. To develop guidelines for treatment and preventative strategies for preterm infants at risk for the development of sBPD
2. To determine the optimal prescription of existing medications in preterm infants with sBPD
3. To determine optimal ventilatory strategies in the neonatal intensive care unit and home settings
4. To identify newer therapeutic agents for the treatment of sBPD

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mechanical ventilation to prevent secondary ventilator-
associated lung injury. Persistent need for mechanical ventilator
support at postnatal day 7 is associated with high risk for
BPD,11 however, the link between BPD risk and sustained
ventilator support at this time point may simply reflect the
critical impacts of adverse antenatal and early postnatal
events on lung structure and not merely be due to ventilator-
associated lung injury alone. Recent multicenter trials no
longer support intubation solely for the purpose of treat-
ment with exogenous surfactant.25-27 Unfortunately, a significant
proportion of infants cannot be stabilized and supported on
nasal CPAP during their entire hospital course. Several recent
trials have shown that infants randomized to immediate
nasal CPAP were intubated secondary to apnea or respira-
tory failure in at least 50% of cases.25-27 Hence, the proportion
of infants exposed to intubation and mechanical ventilation
remains high along with a continued high incidence of
chronic respiratory failure and the subsequent development
of sBPD. In extremely low birth weight infants in the first
week of life, attempts at extubation to and stabilization on
nasal CPAP are still warranted, based on the potential impact
of prolonged ventilator support on sBPD and adverse
neurodevelopmental outcomes.28
However, at some point during the respiratory course of
premature infants with evolving BPD, lung structure and
function may become sufficiently abnormal that attempts at
extubation to nasal CPAP are neither feasible nor desirable.
Some indicators include sustained respiratory distress with
retractions, recurrent cyanotic or bradycardic episodes, intol-
erance of respiratory and physical therapies or handling,
poor growth, and the apparent use of or need for repeated
steroid courses without sustained benefit. At this point, the
goals of care need to be redirected toward optimizing man-
agement on mechanical ventilation to support adequate gas
exchange, reduce the work of breathing, and optimize growth
and healing of the injured lungs. Resolution of the lung
disease and improvement in lung function depends on em-
phasizing nutritional strategies that enhance somatic and
lung growth.
Matching Ventilator Strategies with Lung
Mechanics in sBPD
Determining the specific type and level of respiratory support
for infants with sBPD is challenging, as an optimal ventilator
strategy required by these infants is frequently dramatically dif-
ferent than the strategy utilized in the first few weeks of life
(Table III).29 The strategy must reflect the transition from lung
mechanics in the first few days of life, which are dominated
by low compliance, relative homogeneity, and normal airway
resistance, to the mechanics that are seen in sBPD, domi-
nated by high airway resistance, air trapping, and heteroge-
neous aeration (Figure 2).29 In the first week of life, lung
mechanics suggest that a ventilator strategy aimed at the rela-
tively uniform respiratory system with short time constants
is reasonable and would include a fast rate, low tidal volume
(Vt), short inspiratory time (Ti) strategy (Figure 2).29-31 In sBPD,
the lung is characterized by different combinations of lung
regions with different levels of airway resistance and altered
distal lung compliance, which leads to highly diverse time con-
stants (Figure 2). Thus, to enhance gas exchange, reduce the
risk for atelectasis, decrease dead space ventilation, and perhaps
lower pulmonary vascular resistance, the ventilator support
strategy needs to change dramatically from a fast-rate, low Vt
strategy during the early course to a slow-rate, high Vt and pro-
longed Ti strategy for chronic disease (Table III).
As lung mechanics change over time in infants with sBPD
who are on relatively low concentrations of supplemental
oxygen and moderate or high rates, it is not uncommon to
observe acute episodes (“spells”) of respiratory distress asso-
ciated with high to fraction of inspired oxygen (FiO2) require-
ments, which are often difficult to address by simple maneuvers
on the ventilator. At this stage, hypercarbia is often present with
radiographic findings of hyperinflation alternating with areas
of haziness and atelectasis. The timing of onset of these epi-
sodes in ventilated infants is variable, although these often
develop during the first month of life. Some episodes of acute
deteriorations in oxygenation may represent loss of volume
during forced exhalation, leading to intrapulmonary shunt.32
These events are usually brief and self-limited, but may be

Table III. Comparison of ventilator strategies and goals during progression of early disease to established sBPD (modi-
fied from Abman and Nelin29)
Early (prevention) Strategies to prevent acuteLow tidal volumes (3-5 mL/kg)
lung injury Short inspiratory times (0.2-0.3 seconds)
Increased PEEP for lung recruitment without overdistension
Strategies for gas exchange Adjust FiO2 to target SpO2 (range: 91%-95%)
Permissive hypercapnia
Late (established BPD) Strategies for gas exchange Marked regional heterogeneity
Larger tidal volumes (10-12 mL/kg)
Longer inspiratory times (≥0.6 s)
Airways obstruction
Slower rates allow for better emptying, especially with larger tidal volumes (10-20 bpm)
Complex roles for PEEP with dynamic airway collapse
Interactive effects of ventilator strategies
Changes in rate, tidal volume, inspiratory and expiratory times, and pressure support are highly interdependent
Overdistension can increase agitation and paradoxically worsen ventilation
Strategies for gas exchange Adjust FiO2 to target higher SpO2 (92%-95%)
Permissive hypercapnia to facilitate weaning

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A B

Figure 2. Illustration of A, 2-zone disease vs B, multizone (heterogeneous) disease. A, Chest CT with 2 zones in a patient
with acute respiratory distress syndrome. B, Chest CT in a patient with type 2 sBPD and diffuse, heterogeneous disease. C,
Schematic illustrating concept of multizone disease. Time constant, T = resistance x compliance. Reprinted with permission
from Abman et al.29

frequent. These “breath-holding spells” are likely a separate phe- provide better support to maintain lung volume, and consid-
nomenon from the more prolonged events that may be asso- eration of a trial of drug therapy, such as a steroid “burst,”
ciated with striking elevations of partial pressure of carbon bronchodilators, and/or diuretics. Although many infants get
dioxide (PaCO2), suggesting marked airways obstruction treated with bronchodilators and diuretics, their use between
because of mucus plugging, aspiration, or central airway centers is highly variable.33,34
dynamic collapse. Approaches to severe spells include vigor- A single center study of preterm infants reported that
ous suctioning, airway cultures to diagnose ventilator-associated infants on mechanical ventilation at 30 days with a respira-
pneumonia, transitioning mechanical ventilator strategies to tory severity score of >6 (defined as mean airway
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pressure × FiO2) were more likely to succumb to respiratory
failure and were ventilated longer than infants with a respi-
ratory severity score <6 at that time point.35 These data
suggest that abnormal lung function develops well before 1
month of life and that with progressive respiratory instabil-
ity, one should consider changing the respiratory support
strategy to alter ventilator strategy to include a slow rate,
larger Vt, and increased Ti to maintain minute ventilation
and functional residual capacity.
Whether the use of volume targeted or pressure-limited ven-
tilation is best with sBPD is uncertain, however, chronic re-
spiratory support strategies require higher tidal volumes than
those used with early “lung protective” strategies during the
acute phases of disease.29,31 The targeted Vt for acute short time
constant disease is typically in the range of 4-6 mL/kg, whereas
for infants with developing obstructive airway disease the Vt
may be 8-12 mL/kg. For pressure ventilation, the peak infla-
tion pressure needed to generate this Vt can be well above 25 cm
H2O, depending on the individual patient’s underlying airways
resistance, lung compliance, and related respiratory system me-
chanics. These higher pressure settings reflect the need to
provide sufficient Vt in lung disease that is generally charac-
terized by high total respiratory system resistance and lower
compliance. Furthermore, Ti are usually increased (0.5-0.8
seconds) to allow for better gas distribution into distal lung
units, but longer Ti and increased Vt requires the use of a slow
ventilator rate (often below 20 breaths per minute) to allow
for sufficient emptying to avoid hyperinflation. Faster rates with
increased Vt and prolonged Ti may worsen gas trapping and
patient-ventilator asynchrony. Monitoring flow waveforms can
aid in determining whether expiratory flow has been com-
pleted before the next breath is delivered.
Although generally counterintuitive in the setting of hy-
perinflation, positive end expiratory pressure (PEEP) should
be relatively high (>6-8 cm H2O) to optimize gas exchange,
maintain functional residual capacity, avoid regional atelec-
tasis, and avoid the adverse effects of “inadvertent PEEP.” In
some patients with significant airways closure especially with
tracheomalacia or bronchomalacia, PEEP may need to be even
higher to keep airways open during active exhalation. Flow-
volume loops of patients with sBPD often show expiratory flow
limitation at low lung volumes when lower PEEP levels are used,
which is due to expiratory collapse of poorly supported small
airways and air-trapping. With this pattern, PEEP can usually
be titrated upward until this expiratory flow limitation is re-
solved by visual inspection of flow-volume loops. Questions
regarding the use of this ventilator strategy for established sBPD
include concerns for further inducing volutrauma because of
additional lung overdistension, but when combined with lower
ventilator rates and sufficient expiratory time, additional gas
trapping is rare with this approach. Presently, there are no clini-
cal trials to validate the strategy of low rate and large tidal
volume ventilation, but this strategy is well-grounded with clini-
cal experience and follows our current understanding of the
pathophysiology of sBPD.29,31,36 For the very small number of
patients with severe BPD who do not respond to this me-
chanical ventilation strategy, the practitioner must then con-
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sider rare but important causes of hypoxemia and ventilation-
perfusion mismatch.
Structure-function studies in the nonresponsive patient with
sBPD may identify other abnormalities such as predomi-
nantly restrictive lung disease, tracheobronchomalacia, and/
or other rare causes of ventilation-perfusion mismatch.
In acute care, rapid weaning from mechanical ventilation
is encouraged to avoid the potential adverse effects of pro-
longed intubation and ventilator support. In contrast, the goal
of mechanical ventilation in the chronic phase of the venti-
lated infant with sBPD is to provide relatively stable respira-
tory support to reduce respiratory distress, improve gas
exchange as reflected by lower FiO2, minimize intermittent
“spells,” enhance tolerance of care and handling, and reduce
the need for chronic sedation. Additional goals include pre-
venting the development or progression of PH, providing
optimal nutrition for quality growth, and encouraging devel-
opmental outcomes. These clinical variables of respiratory sta-
bility better reflect successful strategies than traditional metrics
of PaCO2 or end-tidal carbon dioxide (CO2), which are un-
reliable in this setting. There is a slow but steady decrease in
the amount of oxygen needed to provide stable saturations and
sometimes even the Vt can be weaned. The focus should be
on lowering the oxygen concentration in this phase of the
healing disease and once infants are stable in less than 40%
oxygen to achieve oxygen saturation (SpO2)values ≥ 92%, ex-
tubating to noninvasive respiratory support is considered and
is usually successful even from relatively high Vt.
Considerations for Tracheostomy Placement and
Commitment to Chronic Ventilator Support
The decision to commit an infant with sBPD to chronic ven-
tilator support with the placement of a tracheostomy tube can
be complex and difficult and must involve extensive discus-
sions among care providers and family members. Many factors
contribute to this decision, but the overall goal of chronic me-
chanical ventilator support is to reduce the severity of respi-
ratory distress, including retractions, head-bobbing, dyspnea,
and “spells,” to provide clinical stability that will enhance sur-
vival and optimize long-term developmental, neurocognitive,
and growth-related outcomes. Tracheostomy placement is only
part of an organized strategy to provide chronic ventilation
and allows focus to shift toward enhancement of long-term
outcomes. In some settings, tracheostomy represents a symbol
of “futility” that may lead to some reluctance to perform tra-
cheostomy and commit to ventilator support. Tracheostomy
placement should not be viewed as a method for rapidly
weaning of respiratory support but rather a means for sus-
tained mechanical ventilation, relieving distress and provid-
ing the respiratory stability that is necessary to enhance
neurocognitive, behavioral, and developmental outcomes. None-
theless, determination of the efficacy and optimal timing of
tracheostomy for infants with type 2 sBPD remains to be
determined.
Beyond tracheostomy placement, an interdisciplinary team
of collaborating subspecialists and therapists can provide con-
tinuity of care for these children. Teams of experienced
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personnel may coordinate care plans through regular rounds,
family meetings, and collaboration with the attending service
that will alleviate problems attributable to rapid turnover of
staff in the intensive care unit setting. Thus, emphasis should
be directed toward the role of sustained mechanical ventila-
tion to promote growth and development, as supported by an
interdisciplinary care team, and not on simply the placement
of a tracheostomy.
Pulmonary Hypertension in sBPD
Our approach to PH in sBPD is to have a high index of sus-
picion and, when PH is found, to rigorously evaluate pa-
tients for underlying respiratory morbidities and to treat the
lung disease aggressively (Table IV). PH complicates the course
in up to 25% of patients with sBPD,38 therefore, screening
echocardiograms should be performed in all patients with
sBPD. Some cases of PH might be missed with the use of
echocardiography alone;39 nevertheless, it remains the best non-
invasive screening tool to assess PH in sBPD. Even though the
accuracy of the echocardiogram may be limited regarding the
ability to find a measurable and reproducible tricuspid regur-
gitant jet velocity to estimate right ventricular systolic pres-
sure, other markers of PH, such as septal wall flattening and
right ventricular dilation, may be clinically useful.24
If the screening echocardiogram is initially normal, subse-
quent echocardiograms should be performed in patients with
sBPD at 1- to 2-month intervals until the respiratory status
of the patient is significantly improved. If, on the other hand,
the screening echocardiogram demonstrates PH, the initial clini-
cal strategy for the management of PH in infants with BPD
begins with optimizing the treatment of the underlying lung
disease (Table IV).37 Periods of acute hypoxemia, whether in-
termittent or prolonged, contribute to the pathogenesis of late
PH in sBPD and also exacerbate existing PH. Therefore, oxygen
saturation limits may need to be changed to avoid intermit-
tent or sustained hypoxemia with targets generally between 92%
and 95%.37 Indeed, in patients with BPD and severe PH who
also have significant respiratory distress and high levels of re-
spiratory support, the presence of PH may provide a stron-
ger rationale for long-term mechanical ventilatory support with
tracheostomy. Changes in serial blood brain natriuretic peptide
and N-terminal pro-brain natriuretic peptide levels may provide
additional guides to aid the management of PH in sBPD.
Cardiac catheterization can be used to guide therapy, par-
ticularly in severe cases and in cases requiring long-term
therapy.37 Although cardiac catheterization prior to the ini-
tiation of long-term therapy is encouraged, the risks and ben-
efits of this procedure in sick newborns depend on local
expertise with the procedure and severity of disease. The goals
of cardiac catheterization are to assess the severity of PH;
exclude or document the severity of associated anatomic cardiac
lesions; define the presence of systemic-pulmonary collateral
vessels, pulmonary venous obstruction, or left heart dysfunc-
tion; and to assess pulmonary vascular reactivity in patients
who fail to respond to oxygen therapy alone.37 In particular,
several key factors that may affect cardiopulmonary function
include assessment of shunt lesions, especially atrial septal
defects; the presence, size, and significance of bronchial or sys-
temic collateral arteries; the presence of pulmonary vein ste-
nosis; and structural assessments of the pulmonary arterial and
venous circulation by angiography.
Despite the growing use of pulmonary vasodilator therapy
for the treatment of PH in BPD, data demonstrating efficacy
are extremely limited, and these agents should be used only
after thorough diagnostic evaluations and aggressive manage-
ment of the underlying lung disease (Table V).24,37 Current
therapies used for PH therapy in infants with BPD generally
include inhaled nitric oxide (iNO), phosphodiesterase type 5
inhibitors, endothelin receptor antagonists, and calcium channel
blockers (CCBs). In a small number of patients with sBPD un-
dergoing cardiac catheterization, iNO decreased pulmonary
artery pressure and the ratio of pulmonary vascular resis-
tance to systemic vascular resistance, which was further aug-
mented with supplemental oxygen.40 Calcium channel blockers
(such as nifedipine) benefit some patients with PH, and short-
term effects of these agents in infants with BPD have been

Table IV. Considerations for pulmonary hypertension in sBPD (modified from Abman and Nelin;29 Abman et al37)
Diagnoses
1. Screening via echocardiography (assess for tricuspid regurgitant jet velocity, septal flattening, RV dilation, and other parameters of RV function)
a. If no pulmonary hypertension present:
i. Rescreen every 1-2 mo until significant improvement in respiratory status
b. If pulmonary hypertension present:
i. Evaluate and treat respiratory disease, including assessing for hypoxemia, aspiration, and structural disease
ii. Avoid hypoxemia (maintain oxygen saturations between 92% and 95%)
iii. Consider therapeutic agents as below
Pharmacologic treatments
1. Pretreatment: Cardiac catheterization should be considered prior to initiating long-term therapy to assess severity of disease and potential contributing factors,
such as left ventricular diastolic dysfunction, anatomic shunts, pulmonary vein stenosis, and systemic collaterals
2. Therapies
a. iNO can be started at 20 ppm for symptomatic or severe pulmonary hypertension
b. Transition from iNO to sildenafil as feasible starting at 0.5 mg/kg q8h and advancing to 2 mg/kg q6h. Monitor for desaturations secondary to V/Q mismatch
and systemic hypotension.
c. If unable to wean from iNO, consider the addition of an ETRA or a prostacyclin analog. Liver function should be monitored if on an ETRA.
3. Monitoring: Cardiac catheterization or serial echocardiography is recommended to monitor response to therapy

ETRA, endothelin receptor antagonist; RV, right ventricular; V/Q, ventilation-perfusion.

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Table V. Pharmacology of sBPD
Categories Medications
Diuretics Furosemide
(Enteral dosing) Chlorothiazide
Spironolactone
Bronchodilators Albuterol
Ipratropium
Levalbuterol
Inhaled corticosteroids Beclomethasone
Budesonide
Fluticasone
Pulmonary hypertensive agents Bosentan
Sildenafil
Treprostinil
Antireflux agents (enteral dosing) Erythromycin
Lansoprazole
Metoclopramide
Omeprazole
Ranitidine
MDI, metered dose inhaler; PRN, as needed.
reported.41,42 However, CCBs can cause systemic hypotension
and suppress myocardial function, especially in young infants
with left ventricular dysfunction. In comparison with acute iNO
reactivity in a small number of infants studied with sBPD, the
acute response to CCBs was minimal.40
Sildenafil or bosentan (an endothelin receptor antagonist)
are frequently used for long-term therapy of PH in infants with
BPD.43 Sildenafil, a highly selective type 5 phosphodiesterase
inhibitor, augments cyclic guanosine monophosphate content
in vascular smooth muscle and has been shown to benefit adults
with PH as monotherapy and in combination with standard
treatment regimens.44,45 In a study of infants with chronic lung
disease and PH, prolonged sildenafil therapy was associated
with improvement in PH by echocardiogram in most pa-
tients (88%) without significant adverse events.46 Although the
time to improvement was variable, many patients were weaned
from mechanical ventilator support and other PH therapies
during the course of sildenafil treatment without worsening
of PH.46 The recommended starting dose for sildenafil is 0.5 mg/
kg/dose every 8 hours. If there is no evidence of systemic hy-
potension, this dose can be gradually increased over 2 weeks
to achieve desired pulmonary hemodynamic effect or a
maximum of 2 mg/kg/dose every 6-8 hours. Data on other
agents, such as endothelin receptor antagonists and prostacyclin
analogs, are limited in infants with BPD who fail to respond
to other approaches.37 Recent studies suggest that chronic
treprostinil infusion by subcutaneous delivery may provide ad-
ditional benefit in infants with BPD and PH that is poorly re-
sponsive to other medications.47,48
Nutritional Management in sBPD
Infants with sBPD provide unique nutritional challenges partly
because of periods of hypermetabolic states, increased work
of breathing, growth suppression from chronic stress and
inflammation, and chronic steroid or diuretic use. The goal
of nutrition in BPD is to deliver adequate constituents that
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Dosing Comments
1-2 mg/kg/dose q12-24h Often PRN
20-40 mg/kg/d divided q12h
2-4 mg/kg/d divided q12-24h
2.5 mg nebulized or 2 puffs q4-12h Often PRN
0.5 mg q6-12h Often PRN
0.31-1.25 mg or 2 puffs q4-12h Often PRN
2 puffs q12h 40 or 80 mcg MDIs
1 neb q12-24h 0.25 or 0.5 mg nebs
2 puffs q12h 44, 110, 220 mcg MDIs
½ tab BID PO
0.25-0.5 mg/kg/dose q 6-8 h
Starting dose: 2 ng/kg/min iv or SQ
2-4 mg/kg/dose q6-8h
0.5-1.0 mg/kg/dose BID
0.1-0.2 mg/kg/dose q6-8 h
0.5-1.5 mg/kg/d
2-4 mg/kg/d divided q8-12 h
match the patient’s specific needs, but these needs change
with time in infants with sBPD. Optimal nutrition requires
an understanding of multiple factors that can affect somatic
growth and also slow organ growth over time. Long-term
pulmonary outcome studies highlight the persistence of ab-
normalities in lung development even into young adulthood,
demonstrating the complexity of determining the nutri-
tional state in these infants and defining their nutritional
support requirements.
Unfortunately, data regarding optimal nutritional interven-
tions in patients with sBPD are limited. It is known that infants
with sBPD grow more poorly than preterm infants without
BPD, and neonates with the slowest growth velocities are as-
sociated with a high risk for sBPD. Adequate nutrition,
including micronutrient and vitamins A, D, and C supple-
mentation, is likely critical for lung growth, development, func-
tion, and repair. The role of growth factors and their suppression
by stress and inflammation have been shown to underlie the
nutritional imbalance in sBPD, and monitoring of somatic
growth by weight and length is essential. Despite improve-
ments in nutritional intake and growth over the past decade,
infants with sBPD often continue to demonstrate growth failure.
Many studies only report weight gain, although there is strong
recognition of the importance of linear growth. Better nutri-
tional measures have also been shown to correlate with better
neurodevelopmental outcomes in infants with BPD.49
Nutritional assessments should include a review of prena-
tal and past medical history, birth weight z scores, anthropo-
metric data, medication exposure, biochemical data, and clinical
status. Anthropometric data including measurements of weight,
length, and head circumference are the most common methods
used for monitoring postnatal growth and are compared with
reference data. Individual patient data should be plotted and
followed with an infant growth chart to better assess changes
in growth trajectories. Although weight can be measured easily
and accurately, it is influenced by fluid status and may not
always reflect changes in lean body mass. Linear growth is
widely regarded as the best measure of assessing adequacy of
2016
dietary intake and is associated with lean body mass accre-
tion and organ growth and development. Measuring length in
a precise and reproducible manner often poses a challenge. Use
of a recumbent length board to measure crown-heel length
should be a standard of practice in assessing linear growth in
this patient population. Weight for length status should be as-
sessed for proportionality to avoid developing overweight. Per-
sistent weight gain at a rate that crosses growth chart percentiles
without the same pattern demonstrated in linear growth war-
rants a re-evaluation in energy intake and is often associated
with a change in the clinical status of the patient. Intrauter-
ine growth retardation and/or small for gestational age are high-
risk conditions for developing sBPD and may set the stage for
persistent abnormal growth patterns in the postnatal period.
Small for gestational age status has also been associated with
an increased risk for PH in sBPD.50
Caloric demands are likely high to meet the metabolic re-
quirements for growth and healing. This may be achieved with
the use of highly fortified mother’s breast milk or calorically
dense formula feedings. Consistent with American Academy
of Pediatrics recommendations, mother’s breast milk should
be used through the first 6 months of life. Energy intakes
>130 kcal/kg/day may be required in these infants, particu-
larly during the more unstable phase of BPD, whereas older
infants in the more stable respiratory phase of BPD may require
much less depending upon the level of activity and stability.
Although excessive calories may increase CO2 production, past
studies implicate a dietary imbalance of high carbohydrate to
low fat that is particularly problematic in children and adults
with chronic respiratory failure. Adequate protein intake is nec-
essary to promote linear growth, lung growth, and repair of
damaged tissue. Protein needs for the preterm infant are high,
initially ranging from 3.5 to 4.2 g/kg/day. At present, there are
no specific protein recommendations for infants with sBPD.
Providing adequate amounts of protein for corrected gesta-
tional age and perhaps aiming toward the higher range may
be beneficial to compensate for periods of catabolic, hyper-
metabolic states when protein turnover is high. Medications,
such as corticosteroids, also negatively impact protein accre-
tion and body composition; however, no studies are available
for nutritional guidance in this population. Individualized nu-
tritional support with close monitoring and titration is im-
portant to avoid over- or underfeeding in this population.
Although high fluid intake early in the NICU course of
preterm infants is associated with increased risk for BPD, there
are no studies that directly address the role of fluid restric-
tion in established BPD. Fluid intake for subjects with sBPD
is usually in the range of 130-150 mL/kg/day, and it should be
kept in mind that fluid needs decrease over the first year of
life. It is reasonable to use conservative fluid intake in pa-
tients with sBPD, however, adequate delivery of nutrients and
water to meet both nutritional and physiological needs must
be assured. Adequate respiratory support is important from
a nutritional standpoint in these infants because cyanotic spells,
increased work of breathing, and air hunger place these infants
at high risk for linear growth failure because of energy ex-
penditure and stress-induced growth suppression.
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Metabolic bone disease (MBD), also called “osteopenia” or
“rickets of prematurity,” is a common finding in preterm infants,
which is more common and severe in extremely preterm
infants.51-58 After preterm birth several postnatal factors con-
tribute to the risk for MBD, including parenteral and enteral
supplements of calcium and phosphorus that cannot match
in utero sources,59 placement of preterm infants in the NICU
in physical environments that restrict movement,60 and expo-
sure to multiple drug therapies that may affect overall bone
health.61-63 In addition, severe respiratory insufficiency may ex-
acerbate feeding intolerance in infants with sBPD, who then
may require prolonged parental nutrition, which provides in-
adequate calcium and phosphorus and may also lead to alu-
minum accumulation that can have a negative effect on bone
formation.64 The typical biochemical picture of MBD in-
cludes normal serum calcium, low serum phosphorus, and high
serum alkaline phosphatase concentrations.65-67 Radiographs
are an inefficient diagnostic tool for MBD and will not detect
decreases of bone mineralization less than ~20%-30%.68 Bone
density scans more accurately reflect bone demineralization,
but a bone density scan involves radiation exposure, is not a
portable device, and standards for preterm infants are
lacking.69,70 Although short-term effects of poor bone health
seem to resolve with time, long-term stunting effects have been
documented in these infants into their teenage years.63
Aspiration is a potential risk factor for persistent lung injury
in the infant with sBPD. Common sources of aspiration may
include oral intake via dysfunctional swallowing,71 gastro-
esophageal reflux,72 a patient’s own oral secretions, and po-
tentially increased upper respiratory secretions during infections.
Limited recurrent aspiration may result in chronic respira-
tory symptoms, such as coughing, wheezing, or tachypnea (al-
though aspiration in preterm infants can frequently be
“silent”);73 desaturations or hypercarbia;74 or poor weight gain.
More acute episodes of aspiration may result in pneumonia,
tracheitis, or bronchitis, often accompanied by an escalation
of respiratory support. Although aspiration in the preterm
infant is often a function of delayed swallowing function
maturation,71,75 other factors to consider include neurologic
insults or congenital or acquired airway anomalies, such as vocal
cord paresis or laryngeal clefts. Evaluation and ongoing as-
sessments in the NICU by an experienced occupational or
speech therapist is strongly recommended for the infant with
sBPD. Diagnostic tests for dysphagia or reflux lack sensitivity
and specificity for aspiration risk in the infant with sBPD,71
thus, there remains controversy regarding surgical treat-
ment. However, in the appropriate clinical scenario, place-
ment of gastrostomy tubes with or without fundoplication may
be warranted.76
Independently, feeding tubes may need to be considered in
infants who orally feed safely, but do not ingest enough calo-
ries for appropriate growth.
Pulmonary exacerbations because of respiratory syncytial
virus (RSV) infections, reactive airways disease, and other prob-
lems may acutely alter swallowing function77 and baseline gas-
trointestinal motility in the preterm infant with sBPD. Gastric
distension may potentially alter respiratory mechanics, thus,
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impairing ventilation. Impaired motility may increase GERD,
and hence, the risk for aspiration. In addition, increased tachy-
pnea can preclude oral intake in patients who orally feed. Strat-
egies to consider during acute exacerbations include the use
of intravenous fluids or enteral rehydration solutions for gas-
trointestinal rest, time-limited placement of a nasogastric tube
for patients who typically eat/drink orally, and/or the use of
continuous tube feeding.
Summary of Nutritional Management of sBPD
Nutritional success in patients with BPD is complicated by many
factors including lack of prospective data in this population,
likely changing needs of the patient over time, growth sup-
pressive states of the patient, comorbidities, and high meta-
bolic needs at times. However, certain goals and concepts should
be employed to strive for the best outcomes. Linear growth
should be measured accurately and followed closely using ap-
propriate standardized growth curves. Weight for length should
also be followed closely, seeking an ideal target goal of ~50%.
Titrations in nutrition should be considered at least weekly in
concert with a dietician familiar with this population. Strict
attention should be given to the nonpharmacologic support
and comfort of the infant to minimize stress. Furthermore, ad-
equate respiratory support that allows for developmental ac-
tivities and play must be provided because this encourages a
“progrowth” state.
Pharmacologic Therapy for sBPD
Diverse respiratory system abnormalities contribute to altered
lung function in different compartments: central airways, bron-
chioles, and distal lung airspace or parenchyma. In addition,
respiratory system problems regarding central respiratory
control, respiratory muscle function, chest wall compliance,
and others also contribute to BPD severity. Each infant with
sBPD may manifest a greater dysfunction in one part of the
respiratory system than others, and the role of any given drug
therapy depends in part on the physiologic target of that therapy.
However, there is a paucity of data on the effectiveness of
medications for treating infants who have developed sBPD. The
Cochrane Neonatal Systematic Reviews Library contains over
300 reviews with BPD prevention or treatment as the focus
of ~35 of those reviews, the majority of which described studies
with enrollment of infants early in the postnatal course before
the development of sBPD. Evidence supporting the use of phar-
macologic agents is limited and largely based on case reports,
case series, and clinical experience, rather than randomized con-
trolled studies. All should be considered in the broader context
of respiratory support, including invasive and noninvasive ven-
tilation, tracheostomy placement, and nutritional manage-
ment. However, these medications have been formally assessed
for only short-term surrogate outcomes, and marked center-
to-center variability in drug use exists.9 This problem also leaves
unanswered questions about the final risk-to-benefit ratio,
which remains largely unknown for many agents. In Table V,
we have outlined the medications used in sBPD with current
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dosing regiments described below, but these recommenda-
tions are based on anecdotal usage as there is currently no evi-
dence to guide their use in sBPD.
Large Airway Disease
Some infants with sBPD have dynamic airways obstruction
because of tracheomalacia or bronchomalacia, as well as pos-
sible fixed lesions, such as subglottic or tracheal stenosis, granu-
lomas, complete cartilage rings, and other central airway
problems.
Beyond manipulation of PEEP and surgical treatment of spe-
cific endobronchial lesions, effective therapies are largely lacking
for infants with many central airway problems. Attempts to
lower the work of breathing by using less dense gases such as
helium-oxygen mixtures (heliox) or treatment of severe
tracheomalacia by aortopexy have produced mixed results.
Small Airway Disease
The approach to reactive small airway disease is generally analo-
gous to childhood asthma and includes systemic or inhaled
corticosteroids (fluticasone or budesonide), bronchodilators
(mainly albuterol, levalbuterol, or ipratropium), and muco-
lytic therapies. Bronchodilators can lower airway resistance and
improve respiratory compliance, however, whether these effects
provide sustained benefit in infants with sBPD is uncertain.
The use of bronchodilators in sBPD is widely variable between
centers.33 Albuterol and levalbuterol are adrenergic agonists that
are used on various schedules to reduce bronchospasm. Clini-
cally, there can be variability in response to bronchodilators,
which may be a result of genetic variability in b2 adrenergic
receptors as seen in children with asthma. However, this vari-
ability in response has not been systematically assessed in pa-
tients with sBPD. Ipratropium, an anticholinergic agent, is used
by some practitioners for its putative effects in reducing
bronchoconstriction and excess secretions. Inhaled anticho-
linergic agents may decrease gastrointestinal motility and result
in dry/thickened secretions. Ipratropium is often used in com-
bination with albuterol for synergism. However, no trials have
been conducted to determine if combination therapy vs
monotherapy is more efficacious. The use of inhaled dornase
has been suggested for patients with sBPD with thick secre-
tions, although never studied in randomized controlled trials.
Acute exacerbation triggered by inflammation and infection
at the lower and medium airways has been treated with cyclic
inhaled tobramycin, but no definitive trials of its use in sBPD
have been published. Other antibiotics, such as azithromycin,
may also have putative anti-inflammatory benefits.
Systemic or inhaled steroid administration is commonly used
for treating or preventing pulmonary exacerbations in sBPD,
sometimes on a daily or every other day dosing schedule. Ste-
roids may have a variety of beneficial effects as observed in other
populations and diseases including enhanced surfactant pro-
duction, decreased inflammation, decreased airway edema, de-
creased capillary leakage, and decreased lung fibrosis. Use of
systemic steroids is not benign as chronic use at doses typi-
cally used in the population with sBPD may result in de-
creased growth, hypertension, bone demineralization, and
Abman et al
2016
developmental delay. The appropriate dose, time, and type of
steroid need to be evaluated to maximize benefits and mini-
mize risk. Individualizing steroid administration also will require
better ability to predict the clinical course of sBPD to deter-
mine when and how to administer steroids in this population.
Other anti-inflammatory medications, such as the leukotriene
receptor antagonists montelukast or zafirlukast, have been sug-
gested as potentially beneficial in sBPD based on their ben-
efits in asthma and allergies. Montelukast may have benefit in
its ability to provide bronchodilation and to decrease inflam-
mation, although data in sBPD are limited.78
Parenchymal or Distal Airspace Disease
Disease of the distal lung includes decreased alveolarization,
dysmorphic vascular growth with hypertensive remodeling,
dilated lymphatics, prominent intrapulmonary shunt vessels,
and pulmonary edema. Diuretics (including furosemide, spi-
ronolactone, and chlorothiazide) either alone or in combina-
tion, are commonly used on the theory that they are combating
the propensity of infants with BPD to develop pulmonary
edema. Although short-term results of use of these medica-
tions have been favorable for improving lung compliance, no
clinically significant outcomes (such as changes in mortality,
duration of mechanical ventilation, oxygen dependence, length
of hospital stay, etc) have been reported, and the use of di-
uretics in sBPD is highly variable between centers.34 Diuret-
ics can have adverse effects, including hypercalciuria,
nephrocalcinosis, metabolic alkalosis, and striking decreases
in serum potassium, phosphate, and other electrolytes. Nebu-
lized furosemide has been shown to provide short-term im-
provement in lung mechanics without systemic diuretic effects,
but it has never been studied as a long-term therapy.79
Systemic Hypertension
Systemic hypertension can also occur in infants with sBPD,
which may be related to corticosteroid therapy, marked neu-
rohormonal stimulation, renal disease, or other factors.80
Echocardiograms can reveal left ventricular hypertrophy or
asymmetric septal hypertrophy. Hypertension is treated em-
pirically with antihypertensive medications and usually re-
sponds to therapy over time.
Antireflux Medications
Gastric propulsive agents and gastric acid secreting blockers
are often used to reduce the risk of aspiration, but this use has
Table VI. Composition of interdisciplinary teams for the management of sBPD
Disciplines Inpatient (NICU/PICU)
Team leader/coordinator Neonatologist, pulmonologist, critical care physician, hospitalist,
or nurse practitioner
Respiratory Neonatologist or pulmonologist, and respiratory therapists
Cardiac Cardiologist
Airway Otolaryngologist
Gastrointestinal Gastroenterologist and/or nutritionist
Development Neonatologist and therapists (also child life)
Nursing Nurses
Social Social worker/ and/or chaplain
PICU, pediatric intensive care unit.
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not been confirmed in definitive trials. In fact, the routine use
of these agents has been described as unnecessary and poten-
tially harmful in neonatology.81
Respiratory Muscle Stimulants
The use of respiratory muscle stimulants, such as caffeine and
doxapram, has been suggested by a few clinicians based on theo-
retical improvements in lung function that could potentially
obviate the need for prolonged assisted ventilation or trache-
ostomy. However, there is no empirical evidence available ad-
dressing this theoretical use of respiratory muscle stimulants
in established sBPD.
Summary of Pharmacology in sBPD
There are few proven treatments for the management of sBPD.
Given the number of these infants and young children, the se-
verity of their respiratory condition, and their guarded long-
term pulmonary function outlook, phase 2 and eventually phase
3 clinical trials are warranted and desperately needed. Given
the new combination therapies used for adults with chronic
obstructive pulmonary disease, we suggest that trials of the most
promising of these therapies be undertaken in combination
with current therapies beginning at 36-40 weeks for infants
with sBPD. The clinically relevant primary outcomes for these
investigations are to reduce hospital days and reduce severity
of pulmonary dysfunction, perhaps including reduced need
for tracheotomy.
Transitional and Postdischarge Care of
Infants with sBPD
The primary criteria, steps, and goals for discharge should be
met so that the infant/child with sBPD can live and thrive at
home in a safe environment while minimizing recurrent hos-
pitalizations. Improving the outcomes of infants with sBPD
involves well-coordinated, interdisciplinary teams that include
links between inpatient and ambulatory care (Table VI). Infants
with sBPD have longer lengths of initial hospitalizations and
are at increased risk for re hospitalizations because of respi-
ratory illnesses after discharge.82 Furthermore, BPD is associ-
ated with impaired postnatal lung growth,83 and in the absence
of adequate recovery particularly during the first 2 years of life,
these children are at increased risk for chronic obstructive pul-
monary disease in later life. Comorbidities can further
Outpatient
Primary care physician
Neonatologist or pulmonologist
Cardiologist
Otolaryngologist
Gastroenterologist and/or nutritionist
Neonatologist or developmental pediatrician, and therapists
Home nurses
Social worker
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contribute to disease severity,84-88 and failure to recognize or
adequately treat comorbidities can contribute to worse out-
comes. Management of infants with sBPD in the home envi-
ronment requires a healthcare provider who is accessible to the
family, can coordinate patient care among the various
subspecialists, and can recognize rapid changes in the health
of the infant. Critical to outpatient care is a subspecialist with
respiratory expertise who may be either a neonatologist or
pulmonologist with expertise in the older child with BPD and
comfortable with respiratory medication management, and
oxygen and ventilator weaning and titration. This provider
should be available for telephone consultation for families and
other medical professionals for questions regarding respira-
tory management at all times. Subspecialty providers should
be also comfortable counseling families on what to expect and
how to avoid exposures that may worsen outcomes such as
daycare or secondhand smoke.89-92 Outpatient clinic capacity
should be sufficient to handle regular clinic visits with visit fre-
quency dependent on the child’s needs, which could range from
weekly to every 3 months especially during the first 2 years of
life, a period of rapid postnatal lung growth and during which
children with BPD are more likely to be hospitalized for re-
spiratory illnesses.
Discharge Preparation
The risk of death after discharge from the NICU is likely highest
in patients with more severe respiratory disease, patients with
tracheostomies, and patients with a history of pulmonary hy-
pertension. Preterm infants are at higher risk for death at home
compared with full term infants, and infants with BPD may
have abnormal responses to hypoxia, placing them at higher
risk for adverse events at home.93 For preterm infants with PH,
mortality has been reported to be as high as 12%-38%.24 In
infants and children with sBPD, the risk of death in associa-
tion with home mechanical ventilation has reported to be as
high as 19%.94 In addition to mortality, infants with BPD are
subject to significant morbidities. Various studies have re-
ported that between 49% and 58% of infants required read-
mission within the first two years of life.95-97
Adequate caregiver training is essential to address outpa-
tient needs of a child with sBPD and is perhaps the most im-
portant part of a safe discharge to home, as some of the
morbidity and mortality following discharge may be prevent-
able. Before discharge, the team should establish a BPD action
plan (Table VII). Caregivers need to demonstrate profi-
Table VII. sBPD action plan
When to give PRN meds
When to suction or change the tracheostomy tube
When to seek telephone consultation
When to go to the emergency department
When to call 911
Summary of previous and active medical issues
List of healthcare providers
List of medications including dosing and frequency
Current oxygen/ventilator settings
Summary of helpful information for caregivers and healthcare providers not
familiar with the child
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ciency in all aspects of care. The home caregiver must be able
to recognize signs of respiratory distress and illness in their
child and to address emergency health issues in the home en-
vironment, such as emergency tracheostomy changes, need for
inhalational medications, and/or equipment failure.98 Poor ad-
herence to respiratory medications was associated with an in-
creased risk of emergency department visits and rescue inhaled
beta-agonist use and increased activity limitations in infants
with sBPD.99 The same study reported that medication non-
adherence was associated with caregiver concerns regarding
medication efficacy and side effects rather than sociodemo-
graphic or clinical factors, therefore, the risks and benefits of
each therapy should be explained to the caregiver. Overall, it
is highly advisable to have at least 2 caregivers trained for the
appropriate cares, especially for an infant or child with a
tracheostomy.98
In addition to family caregivers, some infants may require
home nursing care as well. Determination of home nursing
hours or visits should be finalized and discussed with the care-
giver and payers prior to discharge. Continuous monitoring
by trained caregivers 24 hours per day, 7 days per week is
required, including substantial home nursing presence.98 Lastly,
anticipatory support from social work should also address po-
tential insurance concerns that may arise from medical costs
in the outpatient setting, travel, and time commitments re-
quired to attend outpatient visits, as well as discussions of
the adjustment process for caring for a chronically ill child at
home, including issues of social isolation and management
of communication issues with multiple health care
professionals.100
Discharge of the Tracheostomy/Ventilator-
Dependent Infant with sBPD
The child with chronic respiratory failure who is dependent
on a tracheostomy and ventilator can create specific chal-
lenges for a successful transition to home. Infants and young
children with tracheostomies with or without home ventila-
tion are at increased risk for mortality because of their un-
derlying lung disease and the potential for unobserved plugging
of their tracheostomy tube or disconnection from the venti-
lator leading to cardiopulmonary arrest. In a retrospective study,
Edwards et al101 reported 47 deaths (21% mortality rate) among
228 children on home ventilation with 49% of deaths being
unexpected, including 19% of deaths being related to trache-
ostomy complications. Although there are no guidelines or con-
sensus statements regarding the outpatient management of
sBPD at the current time, the 2008 the American Academy of
Pediatrics Committee on Fetus and Newborn updated a 1998
policy statement discussing the hospital discharge of the high-
risk neonate, much of which is applicable to infants with
sBPD.102 Approaches to the home care of ventilated infants was
recently addressed by a consensus group of the American Tho-
racic Society.98
In keeping with the imperative to train family members as
caregivers, a comprehensive checklist that addresses specific
issues that may arise with tracheostomy and continue after dis-
charge should be created and completed to address the
Abman et al
2016
personal needs of each child and caregiver prior to dis-
charge. Lastly, a recent study has shown that a well-organized
interdisciplinary team that includes inpatient and outpatient
components can reduce duration of hospitalization and enhance
long-term survival.103
Strategies for Home Ventilation
For infants who are ventilator dependent with type 2 sBPD,
home monitoring with both a pulse oximeter and a cardio-
respiratory monitor should be considered.98 The ability to
monitor saturations is essential for adjusting ventilator and
oxygen support in the outpatient setting, but continuous oxygen
saturation monitoring is often not able to be maintained sec-
ondary to limitations on provision of pulse oximeter probes
and by skin breakdown or burns when using nondisposable
probes. However, use of a pulse oximeter is indicated when
infants are not directly observed. Subspecialty providers should
be comfortable with weaning children from chronic ventila-
tion. Guidelines for weaning from chronic ventilation are un-
certain, but recent recommendations from the American
Thoracic Society suggest that children requiring chronic
ventilation should have a comprehensive medical home
comanaged by a generalist and a respiratory subspecialist.98
Polysomnography is more sensitive than clinic-based assess-
ments for weaning support and may be useful in determin-
ing levels or types of respiratory support and determining
optimal timing for weaning off of home ventilation.104 When
polysomnography is not available, alternative approaches, such
as pulse oximetry and end tidal CO2 monitoring, should be
considered. In some cases, inpatient observation may be re-
quired for ventilator weaning, escalation of support, or capping
of tracheostomies for safety purposes.
Strategies for Home Oxygen Therapy
Children with sBPD on oxygen should be monitored closely
in the outpatient setting, and although the use of home pulse
oximeters for children on oxygen is often necessary, it can cause
many false alarms and stress caregivers. When weaning off
supplemental oxygen, the basic tenet is that pulse oximetry
should be used and oxygen saturations should be main-
tained at or above 92%, particularly if pulmonary hyperten-
sion is present.37 In the home setting, only 100% oxygen can
be delivered via nasal cannula, and, therefore, flow rate is ti-
trated during weaning in the outpatient setting. Few studies
have been performed to determine the appropriate flow rate
from which oxygen can be safely discontinued. In a small pro-
spective study, Simoes et al105 demonstrated that infants on
20 mL/kg or less of oxygen were more successful at weaning
to room air. A recent study of 20 pediatric pulmonary pro-
grams in the US found little consensus regarding weaning strat-
egies from supplemental oxygen, but most used prolonged
home assessments of oxygenation by nocturnal pulse
oximetry.106 It is important to note that in addition to oxygen
saturation, achieving adequate somatic growth and preven-
tion or resolution of the signs of PH are important out-
comes to consider prior to discontinuing supplemental oxygen
Interdisciplinary Care of Children with Severe Bronchopulmonary Dysplasia
FLA 5.4.0 DTD ■ YMPD8787_proof ■ November 28, 2016
MEDICAL PROGRESS
therapy. When growth is poor, the use of nocturnal oxygen may
need to be extended. In summary, for many infants with sBPD,
safe outpatient use of supplemental oxygen can allow infants
to continue to progress in the home environment rather than
in the NICU. Further research is needed to determine optimal
weaning strategies.
Monitoring Lung Function
Infant pulmonary function testing (PFTs) can be useful in as-
sessing severity of lung dysfunction and response to treat-
ment. Limitations to infant PFTs include use of sedation and
lack of availability at many tertiary care centers. All children
with sBPD should undergo regular PFTs when they are able
to follow directions because abnormalities in pulmonary func-
tion are often missed or underestimated in children with BPD.
Small airway dysfunction manifested by hyperinflation and re-
active and fixed small airway obstruction has been reported
in school age children with a history of BPD. 107 Oxygen
desaturation with exercise or with lower respiratory tract ill-
nesses can frequently occur in children with sBPD.108
Management of Respiratory Viruses and Lower
Respiratory Illnesses
Respiratory infections can be life-threatening in children with
sBPD and are more likely to result in hospitalization, includ-
ing a high rate of pediatric intensive care unit admissions. In
a cohort from the United Kingdom, 73% of infants with BPD
required at least 1 readmission in the first 2 years of life and
27% had 3 or more hospitalizations.109 Historically, most ad-
missions in children with BPD have been due to lower respi-
ratory tract infections (LRTIs) secondary to RSV, but human
metapneumovirus and rhinovirus LRTIs are common.110-112
The use of palivizumab, a monoclonal antibody against the
F glycoprotein in RSV, has reduced the morbidity and mor-
tality associated with RSV infection.111,112 Because respiratory
infections can be more severe in children with BPD, these
children require closer monitoring with the onset of viral symp-
toms. Infants who have recently weaned off supplemental
oxygen are more likely to become hypoxic with viral
exposures.113 Although management is focused on support-
ive care and monitoring to ensure that the child remains well
saturated and well hydrated, a trial of inhaled bronchodilators
or inhaled steroids may be helpful.
Although bronchiolitis usually is a self-limited illness, infants
with BPD who require hospitalization for bronchiolitis are at
increased risk for wheezing with subsequent viral exposures.
Thus, the use of preventative measures is critical in this high-
risk population. Vigilance in receiving all doses of palivizumab
during the typical 6-month window of RSV infection reduces
the risk of severe RSV disease, but efforts should be made to
limit the impact of other viral pathogens. The use of hand
hygiene is important, especially with siblings who enter the
home from school or preschool exposures. The increased se-
verity of LRTIs in infants with sBPD may also contribute to
the increased prevalence of cough and wheezing that persists
beyond the acute infection.
13
THE JOURNAL OF PEDIATRICS • www.jpeds.com
Neurodevelopmental Outcomes
Children with sBPD should be evaluated by experts in child
development and be enrolled in an early infant intervention
program that can provide home therapy visits (when pos-
sible) to address developmental issues common in preterm chil-
dren. Nonoxygen-dependent children with BPD have been
reported to catch up developmentally at 2 years of age, whereas
those initially discharged home on oxygen have been re-
ported to catch up by 4 years of age,114 but infants who re-
quired mechanical ventilation at 36 weeks PMA were 6 times
more likely to have quadriparesis compared with infants who
required only supplemental oxygen at 36 weeks PMA.115 Close
neurodevelopmental follow-up can provide parents with re-
assurance and education on appropriate developmental mile-
stone attainment, specific to the child’s chronologic age and
degree of prematurity.
Conclusions
Despite major improvement in the care and outcomes of ex-
tremely preterm infants over the past few decades, some infants
develop especially severe chronic lung disease that includes those
who require prolonged ventilator support (or type 2 sBPD).
More basic and translational research is needed to better un-
derstand the pathobiology of sBPD, including mechanisms that
cause more severe disease than in other preterm infants, as well
as epidemiologic and outcomes research to elucidate risk factors
and patterns that may lead to earlier identification of at risk
infants (Table II). Finally, organized approaches for clinical in-
terventions and trials that involve multiple centers are neces-
sary due to the relatively small numbers of sBPD at each site.
Such approaches may help provide better information to
develop new care guidelines to enhance the long-term out-
comes of infants with sBPD. ■
Submitted for publication Jul 27, 2016; last revision received Sep 20, 2016;
accepted Oct 26, 2016
Reprint requests: Steven H. Abman, MD, University of Colorado School of
Medicine and Children’s Hospital Colorado, Mail Stop B395, 13123 East 16th
Ave, Aurora, CO 80045. E-mail: Steven.abman@ucdenver.edu
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THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume ■■

Jason Z. Stoller, MD, Kathryn Maschhoff, MD; Kristen J.

Appendix McKenna, MD; Nicolas Bamat, MD; Vanderbilt University,
Nashville, TN: Steven Steele, BA; Brown University, Provi-
Additional members of the BPD Collaborative include:
dence, RI: Shukla Khushbu, MD; Baylor University, Houston,
Children’s Mercy, Kansas City, KC: Charisse Lachica, MD,
TX: Sushma Nuthakki, MD; Nationwide Childrens Hospital,
Winston Manimtim, MD, Michael F. Nyp DO MBA, Tamorah
Columbus, OH: Carl H. Backes, MD; Sudarshan Jadcherla, MD;
Lewis, MD, PhD; Children’s Hospital Colorado, Aurora, CO:
Chandar Ramanathan, MD; Kris Reber, MD; Margaret Holston,
Jody Thrasher, RN, Alicia Grenolds, PNP; Childrens Hospital
RN, BSN; Nick Foor; Daniel Malleske, MD; Joe DiMaggio Chil-
of Philadelphia, Philadelphia, PA: Howard Panitch, MD; Erik
dren’s Hospital, Hollywood, FL: Bruce Schulman, MD.
A. Jensen, MD; David A. Munson, MD; William W. Fox, MD;

17.e1 Abman et al

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